This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.

Significance

Pressure overload triggers responses in cardiomyocytes and noncardiomyocytes, leading to pressure overload hypertrophy (POH). Here, we show that cardiac resident macrophages regulate compensatory myocardial adaptation to POH, while nonresident infiltrating macrophages are detrimental. At early-phase POH, pressure overload induces cardiac resident macrophage proliferation, which is regulated by Kruppel-like factor 4. At late-phase POH, pressure overload also induces Ly6Chi monocyte infiltration, and its blockade improves myocardial angiogenesis and preserves cardiac function. Mechanistically, the differential impact of these two macrophage subsets on myocardial angiogenesis may underlie the cardiac phenotype. These findings provide insights regarding the role of cardiac resident and nonresident macrophages, conceptually update the view of myocardial angiogenesis, and identify monocyte infiltration as a therapeutic target for nonischemic cardiomyopathy.

Abstract

Nonischemic cardiomyopathy (NICM) resulting from long-standing hypertension, valvular disease, and genetic mutations is a major cause of heart failure worldwide. Recent observations suggest that myeloid cells can impact cardiac function, but the role of tissue-intrinsic vs. tissue-extrinsic myeloid cells in NICM remains poorly understood. Here, we show that cardiac resident macrophage proliferation occurs within the first week following pressure overload hypertrophy (POH; a model of heart failure) and is requisite for the heart’s adaptive response. Mechanistically, we identify Kruppel-like factor 4 (KLF4) as a key transcription factor that regulates cardiac resident macrophage proliferation and angiogenic activities. Finally, we show that blood-borne macrophages recruited in late-phase POH are detrimental, and that blockade of their infiltration improves myocardial angiogenesis and preserves cardiac function. These observations demonstrate previously unappreciated temporal and spatial roles for resident and nonresident macrophages in the development of heart failure.

Similar Articles

You May Also be Interested in

Researchers report links between warming and predator-prey interactions in the Arctic and suggest that predator activity can influence carbon and nitrogen dynamics in the Arctic, but that warming may alter or reverse such effects.

A study finds that individuals with major depressive disorder had lower blood levels of acetyl-L-carnitine (LAC) than healthy controls, suggesting that LAC might aid the diagnosis of severe, trauma-associated depression.

A study explores historical fire activity associated with bison hunting by indigenous groups in North America, and suggests that fire use by indigenous hunters might have amplified the effect of climate variability on fire activity in the North American Great Plains.